title: Metabolic inhibition impairs ATP-sensitive K+ channel block by sulfonylurea in pancreatic beta-cells.
abstract: The effect of metabolic inhibition on the blocking of beta-cell ATP-sensitive K+ channels (KATP channels) by glibenclamide was investigated using a patch-clamp technique. Inhibition of KATP channels by glibenclamide was attenuated in the cell-attached mode under metabolic inhibition induced by 2,4-dinitrophenol. Under a low concentration (0.1 microM) of ATP applied in the inside-out mode, KATP channel activity was not fully abolished, even when a high dose of glibenclamide was applied, in contrast to the dose-dependent and complete KATP channel inhibition under 10 microM ATP. On the other hand, cibenzoline, a class Ia antiarrhythmic agent, inhibits KATP channel activity in a dose-dependent manner and completely blocks it, even under metabolic inhibition. In sulfonylurea receptor (SUR1)- and inward rectifier K+ channel (Kir6.2)-expressed proteins, cibenzoline binds directly to Kir6.2, unlike glibenclamide. Thus, KATP channel inhibition by glibenclamide is impaired under the condition of decreased intracellular ATP in pancreatic beta-cells, probably because of a defect in signal transmission between SUR1 and Kir6.2 downstream of the site of sulfonylurea binding to SUR1.
authors.affiliation: Department of Metabolism and Clinical Nutrition, Faculty of Medicine, Kyoto University, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Mukai
authors.forename: H
authors.initials: H
authors.lastname: Ishida
authors.forename: S
authors.initials: S
authors.lastname: Kato
authors.forename: Y
authors.initials: Y
authors.lastname: Tsuura
authors.forename: S
authors.initials: S
authors.lastname: Fujimoto
authors.forename: A
authors.initials: A
authors.lastname: Ishida-Takahashi
authors.forename: M
authors.initials: M
authors.lastname: Horie
authors.forename: K
authors.initials: K
authors.lastname: Tsuda
authors.forename: Y
authors.initials: Y
authors.lastname: Seino
mesh_terms: D019297:2,4-Dinitrophenol / Q000494:pharmacology*; D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002478:Cells, Cultured; D005905:Glyburide / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000187:drug effects / Q000502:physiology; D064233:Sulfonylurea Receptors
chemical_list: D018528:ATP-Binding Cassette Transporters; C577509:Abcc8 protein, rat; D000889:Anti-Arrhythmia Agents; D007093:Imidazoles; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000255:Adenosine Triphosphate; D019297:2,4-Dinitrophenol; D005905:Glyburide; C032151:cifenline